Abstract 2213 SCD regulates intestinal stem cell maintenance by modulating endoplasmic reticulum stress

Wnt/β-catenin signaling regulates intestinal stem-cell (ISC) maintenance, self-renewal and differentiation. Wnt signal activation depends on attachment of palmitoleic acid to Wnt mediated by acyltransferase Porcupine. Stearoyl-CoA desaturase (SCD) generates the monounsaturated fatty acid substrate required for Wnt fatty acylation. The intestine expresses 2 isoforms of SCD, SCD1 and SCD2. However, the role of SCD in modulating intestinal stemness is not known. Using 3D intestinal organoid cultures, we found that SCD is essential for intestinal organoid establishment and propagation. ISCs lacking SCD show morphological differences in organoid growth and are not able to propagate in vitro. Additionally, SCD is essential for regulating intestinal epithelial regeneration and stem cell markers including Lgr5 and Lgr4 in organoid culture. Interestingly, we observed that lack of intestinal SCD modulates intestinal epithelial stemness via ER stress induction. Furthermore, MUFA supplementation rescues organoid growth, stem cell marker expression and abrogates ER stress in dKO organoids. Thus, our results identify for the first time an essential role for SCD-derived fatty acids in intestinal homeostasis and regulating stemness. Importantly, these results provide valuable insights into dietary factors regulating intestinal health and disease development, paving the way for new therapeutic approaches for gastrointestinal diseases, particularly those characterized by inflammation and cellular stress. American Heart Association grant 20CDA35310305 and NIH grant R01DK126963 to HS